TDP-43 is a developmentally regulated protein essential for early embryonic development

Chantelle F. Sephton, Shannon K. Good, Stan Atkin, Colleen M. Dewey, Paul Mayer, Joachim Herz, Gang Yu

Research output: Contribution to journalArticle

216 Scopus citations

Abstract

TDP-43 is a DNA/RNA-binding protein implicated in multiple steps of transcriptional and post-transcriptional regulation of gene expression. Alteration of this multifunctional protein is associated with a number of neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin positive inclusions. Whereas a pathological link to neurodegenerative disorders has been established, the cellular and physiological functions of TDP-43 remain unknown. In this study, we show that TDP-43 is a nuclear protein with persistent high-level expression during embryonic development and with progressively decreased protein levels during postnatal development. In mice where the TDP-43 gene (Tardbp) was disrupted using a gene trap that carries a β-galactosidase marker gene, heterozygous (Tardbp+/-) mice are fertile and healthy, but intercrosses of Tardbp+/- mice yielded no viable homozygotic null (Tardbp+/-) mice. Indeed, Tardbp+/- embryos die between 3.5 and 8.5 days of development. Tardbp+/- blastocysts grown in cell culture display abnormal expansion of their inner cell mass. The pattern of β-galactosidase staining at E9.5 Tardbp+/- embryos is predominantly restricted to the neuroepithelium and remains prominent in neural progenitors at E10.5-12.5. TDP-43 is detected in spinal cord progenitors and in differentiated motor neurons as well as in the dorsal root ganglia at E12.5. β-Galactosidase staining of tissues from adult Tardbp+/- mice shows widespread expression of TDP-43, including prominent levels in various regions of the central nervous system afflicted in neurodegenerative disorders. These results indicate that TDP-43 is developmentally regulated and indispensible for early embryonic development.

Original languageEnglish (US)
Pages (from-to)6826-6834
Number of pages9
JournalJournal of Biological Chemistry
Volume285
Issue number9
DOIs
StatePublished - Feb 26 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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